Amidinoureas

ABSTRACT

A novel method of treating gastrointestinal, spasmolytic and ulcerogenic disorders by the administration of amidinoureas is disclosed.

This is a continuation of copending application Ser. No. 942,247 filedSept. 14, 1978, now U.S. Pat. No. 4,204,000, which is acontinuation-in-part application of copending application Ser. No.787,673 filed Apr. 14, 1977, now abandoned, which is a divisionalapplication of copending application Ser. No. 558,187 filed Mar. 31,1975, which is now U.S. Pat. No. 4,060,635.

The present invention relates to a new method for treatinggastrointestinal, spasmolytic and ulcerogenic disorders by theadministration of amidinoureas.

BACKGROUND OF THE INVENTION

The pharmaceutical compositions which have been used as gastricantisecretory and spasmolytic agents have been such as atropine,homatropine, propantheline bromide, dicyclomine hydrochloride and othercompounds which are structurally dissimilar to the biguanides of thisinvention. Due to the anticholinergic properties of these compounds,they are known to produce undesirable side effects such as mydriasis,xerostomia, cyclopegia and other unwanted effects.

There have been a number of 1-aryl biguanides described in theliterature. They have been proposed for use as antidiabetics,anorexigenic or antimalarial agents. J. H. Burn and J.R. Vane, however,in the Brit. J. Pharmacol. (1948), 3:346-9 tested1-(p-chlorophenyl)biguanide for its ability to reduce gastric secretion.Their findings determined that little or no reduction of gastricsecretion was associated with this compound. Contrary to this belief:

We have unexpectedly found that certain amidinoureas possess valuablepharmacologic properties and these compounds then unexpectedly possessuseful gastric antisecretory and spasmolytic properties.

We have also found that these amidinoureas are substantially free of theanticholinergic side effects which accompany gastric antisecretory andspasmolytic agents.

We have further found that these amidinoureas have a low order oftoxicity.

We have still further found a simple and effective method for treatinggastrointestinal disorders and diseases, such as duodenal and pepticulcers.

DESCRIPTION AND PREFERRED EMBODIMENTS

The present invention describes a method for treating gastrointestinalhyperacidity, gastrointestinal spasms or gastrointestinal ulcerations inhuman or mammal in need thereof by the oral or parenteral administrationof an effective amount of an amidinourea of formula I or its tautomericform II when R is hydrogen: ##STR1## where:

R₂, R₃, R₄, R₅ and R₆ may be the same or different and are:

hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

loweralkoxy,

hydroxy,

arloweralkoxy,

acyloxy,

cyano,

haloloweralkoxy or

loweralkylsulfonyl;

R and R' are hydrogen or loweralkyl;

R" and R'" are hydrogen,

loweralkyl,

loweralkenyl,

cycloalkenyl,

cycloalkylloweralkyl,

cycloalkyl,

aralkyl,

loweralkynyl,

haloalkyl,

hydroxyalkyl,

alkoxyalkyl,

cyanoalkyl,

aminoalkyl,

mono- and di-loweralkylaminoalkyl,

carbamoylalkyl,

mono- and di-carbamoylalkyl,

carboxyalkyl,

alkoxycarbonylalkyl,

aralkoxycarbonylalkyl,

formyl,

acyl,

acylalkyl,

alkylsulfonyl or

aralkylsulfonyl;

R" and R'" together may form a 5-7 atom ring which may include 0-2hetero atoms of N, O or S;

R_(n) is hydrogen or it may be loweralkyl provided at least one of R,R', R" and R'" is other than hydrogen; and

the non-toxic acid addition salts thereof.

Compounds of this invention which are preferred include those where:

R₂, R₃, R₄, R₅ and R₆ are hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

hydroxy or

loweralkoxy; and

R' and R_(n) are hydrogen or loweralkyl and

R" and R'" are hydrogen or alkyl; provided R, R', R" and R'" are not allhydrogen at the same time.

The compounds of formula I or II of the present invention exist astautomeric forms when a proton is present on the second nitrogen atom ofthe amidinourea chain. As with tautomers certain compounds wouldnaturally exist in one form or the other depending on their character asdiscussed in Journal of Organic Chemistry, 33, 1968 p. 552.

The more preferred compounds of this invention include those where:

R₂ is hydrogen or loweralkyl;

R₃ and R₅ are hydrogen, hydroxy or loweralkoxy;

R₄ is hydrogen,

loweralkyl,

hydroxy,

loweralkoxy or

halo;

R₆ is hydrogen,

loweralkyl,

nitro,

alkoxy or

halo;

R and R_(n) are hydrogen or loweralkyl; and

R' and R" are hydrogen or alkyl; provided R, R', R" and R'" are not allhydrogen at the same time.

The most preferred compounds of this invention are those where:

R₂ is hydrogen,

methyl or ethyl;

R₃ is hydrogen,

hydroxy or

methoxy;

R₄ is hydrogen,

methyl,

ethyl,

hydroxy,

methoxy,

chloro or

bromo;

R₅ is hydrogen,

hydroxy or

methoxy;

R₆ is hydrogen,

methyl,

ethyl,

nitro,

methoxy,

ethoxy,

chloro,

bromo or

fluoro;

R and R_(n) are hydrogen,

methyl or

ethyl; and

R' and R" are hydrogen,

methyl,

ethyl,

propyl,

i-propyl,

butyl,

i-butyl,

sec-butyl,

t-butyl,

pentyl,

hexyl or;

heptyl; provided R, R', R" and R'" are not all hydrogen at the sametime.

A special embodiment of this invention comprises compounds which have:

R₂ -loweralkyl substitution;

R₂, R₆ -diloweralkyl substitution;

R₂, R₆ -loweralkyl, alkoxy substitution;

R₂, R₆ -loweralkyl, halo substitution;

R₂, R₆ -alkyl, nitro substitution;

R₂, R₄, R₆ -triloweralkyl substitution, or

R₂, R₄, R₆ -loweralkyl, dihalo substitution.

A further special embodiment of this invention comprises compounds whichhave:

R₃, R₄ -hydroxy or alkoxy substitution;

R₃, R₄, R₅ -hydroxy or alkoxy substitution;

R₂, R₅ -dihalo substitution or

R₂, R₆ -dihalo substitution.

A further special embodiment of this invention comprises compounds whichhave:

R, R', R" and R'" as hydrogen or loweralkyl substitution provided allare not hydrogen at the same time; or

R and R' are hydrogen or loweralkyl and R" and R'" are an alkyl groupfrom 3 to 7 carbon atoms.

The compounds of formula I form the subject matter of U.S. Pat. No.4,060,635, Nov. 29, 1977 which is incorporated herein by reference.

The compounds corresponding to formula I are useful in treatinggastrointestinal disorders such as hyperacidity, spasms and peptic andgastric ulcers. For these purposes they can be administered orally,parenterally or rectally. Administration by the oral route is preferred.Orally, these compounds may be administered in tablets, hard or softcapsules, aqueous or oily suspensions, dispersible powders or granules,emulsions, syrups or elixers. The optimum dosage, of course, will dependon the particular compound being used and the type and severity of thecondition being treated. In any specific case, the appropriate dosageselected will further depend on factors of the patient which mayinfluence response to the drug; for example, general health, age,weight, etc. of the subject being treated.

Although the optimum quantities for administration of the compounds I inaccordance with the present invention will depend on the compoundemployed and the particular type of disease condition treated, oral doselevels of preferred compounds when administered to a mammal in dosagesof 0.05 to 50 milligrams per kilogram of body weight per day areparticularly useful. The preferred range is 0.1 to 20 mg/kg. Comparativedosages may be used in parenteral or rectal administration.

Compositions intended for oral use may be prepared according to methodsknown to the art for the manufacture of pharmaceutical compositions.Such compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents,preserving agents, etc. in order to provide a pharmaceutically elegantand palatable preparation.

Further, the active amidinourea may be administered alone or inadmixture with other agents having the same or different pharmacologicalproperties.

The composition may contain such selected excipients such as inertdiluents such as calcium carbonate, lactose, etc.; granulating anddisintegrating agents such as maize starch, alginic acid, etc.;lubricating agents such as magnesium stearate, etc.; binding agents suchas starch gelatin, etc.; suspending agents such as methylcellulose,vegetable oil, etc.; dispersing agents such as lecithin, etc.;thickening agents such as beeswax, hard paraffin, etc.; emulsifyingagents such as naturally-occurring gums, etc.; non-irritating excipientssuch as cocoa butter, polyethylene glycols, etc.; and the like. Further,in formulating these compounds for every 100 parts by weight of thecomposition, there may be present between 5 and 95 parts by weight ofthe active ingredient. The dosage unit form will generally containbetween 0.1 mg. and about 500 mg. of the active ingredients of thisinvention. The preferred unit dose is between 1 mg. and about 50 mg. Thecompositions may be taken 1-8 times daily depending on the dosage unitrequired.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective in thetreatment of ulcerogenic disease conditions or symptoms, such asduodenal and peptic ulcer. In general, the daily dose can be betweenabout 0.1 mg/kg and 70 mg/kg (preferably in the range of 1-25mg/kg/day), bearing in mind, of course, that in selecting theappropriate dosage in any specific case, consideration must be given tothe patient's weight, general health, age and other factors which mayinfluence response to the drug.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with anti-ulcerogenic activity in humans. These tests involvesuch as the effect of the amidinoureas of the formula I on gastricsecretion, gastrointestinal spasm and their mucogenic effect. It hasbeen found that the compounds of this invention when tested in the abovevariety of situations, show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspost-drug administration, the stomach is removed and its contents areassayed for volume, pH and total acids.

A second gastric secretion test is carried out on dogs. This is outlinedin the Handbook of Physiology, Section 6: Alimentary Canal, Volume II:Secretion, American Physiology Society, Washington, D.C., 1967.

It has been found that the compounds of this invention when subjected tothe above gastric secretion tests display a marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and is a standard test used todetermine antisecretory properties.

To determine the anti-ulcer effectiveness the following test isemployed: Male Wistar rats (130-150 grams) are fasted for 24 hours, thengiven reserpine at 5 mg/kg i.p. Twenty-four hours later, the stomachsare removed and examined for ulceration. Ulcers are graded on a 0-4scale and the number of ulcers is recorded. Pretreatment with the1,5-disubstituted biguanide compounds of this invention produces adecrease in ulcer grade and the number of ulcers compared to the controlreserpine-treated rats.

Determination of antispasmodic properties can be carried out by theprocedure as outlined by D. A. Brodie and S. K. Kundrats in theirarticle entitled "Effect of Drugs on Gastric Emptying in Rats", Fed.Proc. 24:714 (1965).

The biguanides of this invention have also been found to be mucogenicagents, that is, they increase the biosynthesis of mucopolysaccharidesof the gastric mucous membrane which is a mechanism for inhibitinggastrointestinal ulcer. This property is determined by the test outlinedin the J. Pharm. Parmac., 1970, 22, 143-4.

Mydriasis is detected by the procedure R. A. Turner, Screening Methodsin Pharmacology, Academic Press, New York, and London, pp, 174-5, 1965.Acute toxicity is calculated according to the standardLitchfield-Wilcoxon procedure.

In view of the results of these tests the pharmacological data clearlyindicates that the amidinoureas of the formula I substituted biguanidesof this invention can be considered to be effective anti-ulcerogenicagents having active gastric antisecretory and antispasmodic propertieswhich are substantially free of anticholinergic side effects and havinga low toxicity.

We claim:
 1. An amidinourea compound of the general formula I or itstautomeric form II wherein R is hydrogen: ##STR2## where: R₂, R₃, R₄, R₅and R₆ may be the same or different and are hydrogen,haloloweralkyl,nitro, arloweralkoxy, acyloxy, cyano, haloloweralkoxy, orloweralkylsulfonyl; R and R' are hydrogen or loweralkyl; R" and R'" arehydrogen,loweralkyl, loweralkenyl, cycloalkenyl up to 9 carbon atoms,cycloalkylloweralkyl, cycloalkyl, aralkyl, loweralkynyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cyanoalkyl, aminoalkyl, mono- anddi-loweralkylaminoalkyl, carbamoylalkyl, mono- and di-carbamoylalkyl,carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, formyl, acyl,acylalkyl, alkylsulfonyl or aralkylsulfonyl; R_(n) is hydrogen orloweralkyl provided at least one of R, R', R" and R'" is other thanhydrogen; and the non-toxic acid addition salts thereof.
 2. Theamidinourea compound of claim 1 wherein:R₂, R₃, R₄, R₅ and R₆ may be thesame or different and arehydrogen, arloweralkoxy, acyloxy, cyano, orhaloloweralkoxy, provided they are not all hydrogen at the same time. 3.The amidonourea compound of claim 2 wherein:R and R' are hydrogen orloweralkyl, provided R and R' are not all hydrogen at the same time; R"and R'" are hydrogen,loweralkyl, loweralkenyl, cycloalkenyl up to 9carbon atoms, cycloalkylloweralkyl, loweralkyl, cycloalkyl, aralkyl,loweralkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl,aminoalkyl, mono- and di-loweralkylaminoalkyl, carbamoylalkyl, mono- anddi-carbamoylalkyl, carboxyalkyl, alkoxycarbonylalkyl,aralkoxycarbonylalkyl, formyl, acyl, acylalkyl, alkylsulfonyl oraralkylsulfonyl, provided R" and R'" are not all hydrogen at the sametime.